The objective of this proposal is to determine the neural circuits and cellular mechanisms which produce a state of generalized enhanced excitability in the lamprey brain. This active state is proposed as a model for arousal in the vertebrate brain stem. The advantages of the lamprey brain stem for this study are its relative simplicity, similar principles of organization as in other vertebrates, the ability of the isolated preparation to produce activities corresponding to behavior and at the same time to be suitable for intracellular recordings and pharmacological modulation, and background studies by the P.I. on the subsystems which are involved in the active state. The lamprey brain in vitro and lampreys in vivo display resting and active states. Active episodes in vitro occur or in response to sensory stimuli and are expressed as increased activities in trigeminal and spinal motor pathways, enhanced rate and intensity of fictive breathing, and altered responsiveness to sensory stimuli. Corresponding behavioral changes in vivo are active attachment by the sucker, changes in breathing rate, body movements, and altered responsiveness to vibration. The strategy of this proposal is (a) to use the known organization of the trigeminal, respiratory, reticulospinal, and sensory systems in the brain stem to assay behavioral changes in vivo and neurophysiological changes in vitro during the active state, (b) to use lesions, extracellular recording, and focal stimulation to localize critical brain regions involved in the active state, (c) to use receptor agonists and antagonists, including cholinergic and aminergic drugs, to initiate or block components of the active state in vitro, (d) to use intracellular recordings from target neurons to determine changes in cellular properties and monosynaptic transmission during the active state, (e) to identify brain stem interneurons which are involved in the active state, and (f) to integrate this information as cellular and circuit-related models for neural modulation during an arousal-like state in the isolated brain stem of a simpler vertebrate.